目的:探讨M2型肿瘤相关巨噬细胞(M2 type tumor-associated macrophage,M2-TAMs)介导白细胞介素6(interleukin-6,IL-6)-Janus激酶2(Janus kinase 2,JAK2)/信号转导及转录激活因子3(signal transducer and activator of transcription 3,...目的:探讨M2型肿瘤相关巨噬细胞(M2 type tumor-associated macrophage,M2-TAMs)介导白细胞介素6(interleukin-6,IL-6)-Janus激酶2(Janus kinase 2,JAK2)/信号转导及转录激活因子3(signal transducer and activator of transcription 3,STAT3)轴促进胃癌干性和侵袭迁移的作用机制。方法:应用TCGA数据库分析胃癌及癌旁正常组织M2-TAMs的分布与干性指标的关系,并在胃癌患者组织水平进行验证。体外通过成球实验检测胃癌细胞的干性潜能并构建M2-TAMs体外共培养体系,运用qRT-PCR和Western blot技术检测肿瘤干性标志物CD44和醛脱氢酶1(aldehyde dehydrogenase 1,ALDH1)的变化,通过Transwell实验探究胃癌迁移、侵袭能力的变化。利用转录组测序筛选差异基因,通过KEGG富集分析探寻关键通路,并采用中和抗体及通路抑制剂进行相关性验证。结果:TCGA数据库分析和体内组织验证结果均表明胃癌组织中M2-TAMs的密度显著高于癌旁正常组织,且其数量的增加与肿瘤干性标志(CD44和ALDH1)呈正相关。与M2-TAMs共培养的胃癌细胞在CD44和ALDH1的mRNA及蛋白表达水平较对照组显著升高,同时共培养组肿瘤细胞成球率和侵袭迁移能力均显著增强,JAK2/STAT3信号通路关键蛋白表达水平显著升高。KEGG通路分析发现STAT3是肿瘤干性调控的关键基因。与极化前的巨噬细胞相比,极化的M2-TAMs有22个上调分泌因子,其中IL-6显著升高,且与患者不良预后相关。加入stattic(选择性STAT3信号通路抑制剂)和(或)IL-6中和抗体均能抑制胃癌细胞的干性、迁移和侵袭。以上结果P值均<0.05。结论:M2-TAMs通过分泌IL-6介导JAK2/STAT3信号通路激活胃癌细胞干性潜能,进而促进胃癌的侵袭和迁移。展开更多
The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regul...The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.展开更多
文摘目的:探讨M2型肿瘤相关巨噬细胞(M2 type tumor-associated macrophage,M2-TAMs)介导白细胞介素6(interleukin-6,IL-6)-Janus激酶2(Janus kinase 2,JAK2)/信号转导及转录激活因子3(signal transducer and activator of transcription 3,STAT3)轴促进胃癌干性和侵袭迁移的作用机制。方法:应用TCGA数据库分析胃癌及癌旁正常组织M2-TAMs的分布与干性指标的关系,并在胃癌患者组织水平进行验证。体外通过成球实验检测胃癌细胞的干性潜能并构建M2-TAMs体外共培养体系,运用qRT-PCR和Western blot技术检测肿瘤干性标志物CD44和醛脱氢酶1(aldehyde dehydrogenase 1,ALDH1)的变化,通过Transwell实验探究胃癌迁移、侵袭能力的变化。利用转录组测序筛选差异基因,通过KEGG富集分析探寻关键通路,并采用中和抗体及通路抑制剂进行相关性验证。结果:TCGA数据库分析和体内组织验证结果均表明胃癌组织中M2-TAMs的密度显著高于癌旁正常组织,且其数量的增加与肿瘤干性标志(CD44和ALDH1)呈正相关。与M2-TAMs共培养的胃癌细胞在CD44和ALDH1的mRNA及蛋白表达水平较对照组显著升高,同时共培养组肿瘤细胞成球率和侵袭迁移能力均显著增强,JAK2/STAT3信号通路关键蛋白表达水平显著升高。KEGG通路分析发现STAT3是肿瘤干性调控的关键基因。与极化前的巨噬细胞相比,极化的M2-TAMs有22个上调分泌因子,其中IL-6显著升高,且与患者不良预后相关。加入stattic(选择性STAT3信号通路抑制剂)和(或)IL-6中和抗体均能抑制胃癌细胞的干性、迁移和侵袭。以上结果P值均<0.05。结论:M2-TAMs通过分泌IL-6介导JAK2/STAT3信号通路激活胃癌细胞干性潜能,进而促进胃癌的侵袭和迁移。
基金supported by grants from Simons Foundation (SFARI 479754),CIHR (PJT-180565)the Scottish Rite Charitable Foundation of Canada (to YL)funding from the Canada Research Chairs program。
文摘The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.
